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Medicine Jul 2020The purpose of the current meta-analysis was to compare the oncological outcomes of pemetrexed versus gefitinib in pre-treated advanced or metastatic non-small cell lung... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The purpose of the current meta-analysis was to compare the oncological outcomes of pemetrexed versus gefitinib in pre-treated advanced or metastatic non-small cell lung cancer (NSCLC) patients.
METHODS
Search the online electronic databases on comparison the effectiveness and adverse effects of pemetrexed versus gefitinib in therapy outcomes of pre-treated NSCLC to September 2019. All studies analyzed the summary odds ratios (ORs) of the main outcomes, including survival efficacy and toxicity complications.
RESULTS
In all, 5 trials involving 676 subjects were included, with 332 receiving pemetrexed and 344 using gefitinib. The pooled analysis of overall survival (OS) (OR = 0.97, 95%CI = 0.77-1.21, P = .76) and progression-free survival (PFS) (OR = 1.17, 95%CI = 0.60-2.30, P = .65) showed that pemetrexed did not achieve benefit when compared with gefitinib. In the results of subgroup analysis among the EGFR mutation-positive patients, the comparison of gefitinib therapy versus pemetrexed did show PFS benefit 0.35 (95%CI 0.12-1.01; P = .05). In terms of grade 3 or 4 side effects, a similar toxicity profile of both pemetrexed and gefitinib was shown in the incidence rate of rash (P = .045), fatigue (P = .97), thrombocytopenia (P = .68) and anemia (P = .21) between the 2 groups.
CONCLUSION
Pemetrexed was not associated with survival benefit than gefitinib therapy among pre-treated NSCLC patients. While, gefitinib showed superior PFS efficacy than pemetrexed for patients with EGFR mutation-type. Future investigations are required to identify relevant biomarkers in selected patients that would most likely benefit from pemetrexed or gefitinib treatment in pre-treated advanced NSCLC patients.
Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Gefitinib; Humans; Male; Pemetrexed; Progression-Free Survival
PubMed: 32702875
DOI: 10.1097/MD.0000000000021170 -
JTO Clinical and Research Reports May 2022Randomized controlled trials have investigated different first-line treatments for patients with advanced -mutated NSCLC. Nevertheless, their efficacy, in particular,...
Overall Survival Benefits of First-Line Treatments for Asian Patients With Advanced EGFR-Mutated NSCLC Harboring L858R Mutation: A Systematic Review and Network Meta-Analysis.
INTRODUCTION
Randomized controlled trials have investigated different first-line treatments for patients with advanced -mutated NSCLC. Nevertheless, their efficacy, in particular, the long-term overall survival (OS) benefit in Asian patients with L858R mutation, remains unclear.
METHODS
We performed a systematic review and frequentist network meta-analysis by retrieving relevant literature from PubMed/MEDLINE, Ovid, EMBASE, Cochrane Library, trial registries, and other sources. We included randomized controlled trials comparing two or more treatments in the first-line setting for Asian patients with L858R mutation. This study was registered in the Prospective Register of Systematic Reviews (CRD 42022295897).
RESULTS
There were a total of 18 trials that involved 1852 Asian patients and 12 treatments, including the following: tyrosine kinase inhibitors (TKIs) (osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed-based chemotherapy, pemetrexed-free chemotherapy, and combination treatments (gefitinib plus apatinib, erlotinib plus ramucirumab, erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy). Asian patients with L858R mutation had no significant OS benefits from all these treatments. Gefitinib plus pemetrexed-based chemotherapy, dacomitinib, osimertinib, and erlotinib plus bevacizumab were found to be consistent in yielding the best progression-free survival benefit ( scores = 93%, 79%, 77%, and 70%). Combination treatments caused more toxicity, especially erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy, resulting in the greatest incidence of grade greater than or equal to 3 adverse events.
CONCLUSIONS
In Asian patients harboring L858R mutation, TKIs and combination treatments had no OS benefit when compared with conventional chemotherapies. Further studies are warranted to investigate the resistance mechanism with TKIs and potential combination strategies in patients with this common but less favorable mutation.
PubMed: 35516725
DOI: 10.1016/j.jtocrr.2022.100322 -
Medicine Aug 2021When the patients of advanced non-squamous non-small cell lung cancer (NSCLC) have achieved remission by induction therapy, it is controversial that combination with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
When the patients of advanced non-squamous non-small cell lung cancer (NSCLC) have achieved remission by induction therapy, it is controversial that combination with bevacizumab is used as maintenance therapy. Pemetrexed is a classic drug for maintenance therapy, is bevacizumab the superiority to pemetrexed is also unclear. This meta-analysis aims to evaluate the effectiveness and safety of advanced non-squamous NSCLC in the maintenance treatment.
METHOD
From the establishment as of December 6, 2020, PubMed, Embase, and Cochrane electronic databases were searched and the American Society of Clinical Oncology, European Society of Medical Oncology, and National Comprehensive Cancer Network databases in the past 10 years. The application of combination with bevacizumab, pemetrexed was studied in clinical trials of maintenance treatment for advanced NSCLC. The extracted data include progression-free survival (PFS), overall survival (OS), and grade 3-4 adverse events (AE).
RESULTS
Seven clinical trials we screened, 6 were phase III RCTs, and a cohort trial, including 3298 patients. Compared with bevacizumab and pemetrexed, PFS of combination with bevacizumab was significantly improved (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.65-0.77, P < .00001), but OS was not improved (HR = 0.93, 95% CI = 0.85-1.01, P = .10). Compared with bevacizumab and pemetrexed, no significant difference of PFS (HR = 0.87, 95% CI = 0.69-1.09, P = .21), and OS (HR = 0.87, 95% CI = 0.72-1.05, P = .15) was found. A higher incidence of grade 3-4 AE occurred in combination with bevacizumab (odds ratio = 1.63, 95% CI = 1.35-1.97, P < .00001).
CONCLUSIONS
PFS was significantly improved in patients with advanced non-squamous NSCLC who use bevacizumab combination with single-agent as maintenance treatment, but it does not translate into the advantages of OS; compared with bevacizumab, no PFS and OS benefits were found. A higher incidence of grade 3-4 AE occurred in combination with bevacizumab than pemetrexed and bevacizumab.
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Medication Therapy Management; Pemetrexed; Treatment Outcome
PubMed: 34397863
DOI: 10.1097/MD.0000000000026862 -
Annals of Palliative Medicine Jul 2020To compare the survival outcomes of first-line treatment regimens for advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients... (Meta-Analysis)
Meta-Analysis
BACKGROUND
To compare the survival outcomes of first-line treatment regimens for advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with stable brain metastases.
METHODS
We conducted a systematic review of available data from randomized controlled trials (RCTs) of first-line treatment regimens of NSCLC patients with stable brain metastases. Progression free survival (PFS) and overall survival (OS) were extracted and analysed from the RCT subgroups. A network meta-analysis was constructed using the Bayesian statistical model to synthesize the survival outcomes of all the treatments.
RESULTS
The analysis included 6 eligible RCT subgroups with 417 patients and 7 treatment regimens osimertinib, afatinib, first-generation EGFR-TKI (gefitinib or erlotinib), erlotinib + bevacizumab, gefitinib + pemetrexed + carboplatin, gemcitabine + cisplatin, and pemetrexed + cisplatin. Of these seven treatment regimens, gefitinib + pemetrexed + carboplatin had the highest potential for favorable PFS and OS, followed by osimertinib, in the treatment of advanced EGFR-mutant NSCLC patients with stable brain metastases. None of the results met the predetermined statistical significance of P<0.05.
CONCLUSIONS
The regimens of "Gefitinib + pemetrexed + carboplatin" and "Osimertinib" were associated with the most favorable PFS and OS compared to the other therapies in advanced EGFR-mutant NSCLC patients with stable brain metastases, although the difference between these regimens and the others was not statistically significantly different.
Topics: Bayes Theorem; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Survival Analysis
PubMed: 32692221
DOI: 10.21037/apm-20-1136 -
Value in Health : the Journal of the... Jan 2023This study aimed to compare the relative efficacy of lorlatinib, an anaplastic lymphoma kinase-tyrosine kinase inhibitor, with chemotherapy, for patients with...
Matching-Adjusted Indirect Comparisons of Lorlatinib Versus Chemotherapy for Patients With Second-Line or Later Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer.
OBJECTIVES
This study aimed to compare the relative efficacy of lorlatinib, an anaplastic lymphoma kinase-tyrosine kinase inhibitor, with chemotherapy, for patients with second-line or later advanced anaplastic lymphoma kinase-positive non-small cell lung cancer. The endpoints of interest were overall survival (OS) and progression-free survival (PFS).
METHODS
Evidence for lorlatinib was informed by the single-arm phase I/II trial B7461001. A systematic literature review (SLR) was performed to identify OS and PFS data for chemotherapy. Unanchored matching-adjusted indirect comparisons (MAICs) between lorlatinib and chemotherapy (pemetrexed/docetaxel, platinum-based, or systemic therapy) were performed.
RESULTS
The SLR identified 3 relevant studies reporting PFS. Lorlatinib was associated with a significant decrease in the hazard of progression versus the 2 types of chemotherapy assessed. For PFS, the MAIC of lorlatinib versus the combined treatment arm of docetaxel or pemetrexed resulted in an adjusted hazard ratio (HR) of 0.22 (95% confidence interval [CI] 0.15-0.31). When lorlatinib was compared with platinum-based chemotherapy through an MAIC, the adjusted HR for PFS was 0.40 (95% CI 0.29-0.55). An exploratory comparison was performed for OS with evidence for systemic therapy (assumed equivalent to chemotherapy) not identified in the SLR. Lorlatinib provided a significant decrease in hazard of death (OS) versus systemic therapy, with HRs ranging from 0.12 (95% CI 0.05-0.27) to 0.43 (95% CI 0.27-0.60).
CONCLUSIONS
Lorlatinib demonstrated a significant improvement in PFS compared with chemotherapy, although limitations in the analyses were identified. The evidence informing OS comparisons was highly limited but suggested benefit of lorlatinib compared with systemic therapy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Anaplastic Lymphoma Kinase; Docetaxel; Pemetrexed; Lung Neoplasms; Lactams, Macrocyclic; Protein Kinase Inhibitors
PubMed: 35985941
DOI: 10.1016/j.jval.2022.07.002 -
The Cochrane Database of Systematic... Mar 2021Epidermal growth factor receptor (EGFR) mutation positive (M+) non-small cell lung cancer (NSCLC) is an important subtype of lung cancer comprising 10% to 15% of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Epidermal growth factor receptor (EGFR) mutation positive (M+) non-small cell lung cancer (NSCLC) is an important subtype of lung cancer comprising 10% to 15% of non-squamous tumours. This subtype is more common in women than men, is less associated with smoking, but occurs at a younger age than sporadic tumours.
OBJECTIVES
To assess the clinical effectiveness of single-agent or combination EGFR therapies used in the first-line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). The primary outcomes were overall survival and progression-free survival. Secondary outcomes included response rate, symptom palliation, toxicity, and health-related quality of life.
SEARCH METHODS
We conducted electronic searches of the Cochrane Register of Controlled Trials (CENTRAL) (2020, Issue 7), MEDLINE (1946 to 27th July 2020), Embase (1980 to 27th July 2020), and ISI Web of Science (1899 to 27th July 2020). We also searched the conference abstracts of the American Society for Clinical Oncology and the European Society for Medical Oncology (July 2020); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles.
SELECTION CRITERIA
Parallel-group randomised controlled trials comparing EGFR-targeted agents (alone or in combination with cytotoxic agents or BSC) with cytotoxic chemotherapy (single or doublet) or BSC in chemotherapy-naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent.
DATA COLLECTION AND ANALYSIS
Two review authors independently identified articles, extracted data, and carried out the 'Risk of bias' assessment. We conducted meta-analyses using a fixed-effect model unless there was substantial heterogeneity, in which case we also performed a random-effects analysis as a sensitivity analysis.
MAIN RESULTS
Twenty-two trials met the inclusion criteria. Ten of these exclusively recruited people with EGFR M+ NSCLC; the remainder recruited a mixed population and reported results for people with EGFR M+ NSCLC as subgroup analyses. The number of participants with EGFR M+ tumours totalled 3023, of whom approximately 2563 were of Asian origin. Overall survival (OS) data showed inconsistent results between the included trials that compared EGFR-targeted treatments against cytotoxic chemotherapy or placebo. Erlotinib was used in eight trials, gefitinib in nine trials, afatinib in two trials, cetuximab in two trials, and icotinib in one trial. The findings of FASTACT 2 suggested a clinical benefit for OS for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, as did the Han 2017 trial for gefitinib plus cytotoxic chemotherapy, but both results were based on a small number of participants (n = 97 and 122, respectively). For progression-free survival (PFS), a pooled analysis of four trials showed evidence of clinical benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.31; 95% confidence interval (CI) 0.25 to 0.39 ; 583 participants ; high-certainty evidence). A pooled analysis of two trials of gefitinib versus paclitaxel plus carboplatin showed evidence of clinical benefit for PFS for gefitinib (HR 0.39; 95% CI 0.32 to 0.48 ; 491 participants high-certainty evidence), and a pooled analysis of two trials of gefitinib versus pemetrexed plus carboplatin with pemetrexed maintenance also showed evidence of clinical benefit for PFS for gefitinib (HR 0.59; 95% CI 0.46 to 0.74, 371 participants ; moderate-certainty evidence). Afatinib showed evidence of clinical benefit for PFS when compared with chemotherapy in a pooled analysis of two trials (HR 0.42; 95% CI 0.34 to 0.53, 709 participants high-certainty evidence). All but one small trial showed a corresponding improvement in response rate with tyrosine-kinase inhibitor (TKI) compared to chemotherapy. Commonly reported grade 3/4 adverse events associated with afatinib, erlotinib, gefitinib and icotinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms; fatigue and anorexia were also associated with some chemotherapies. Seven trials reported on health-related quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, two trials showed improvement in one or more indices for the TKI compared to chemotherapy. The quality of evidence was high for the comparisons of erlotinib and gefitinib with cytotoxic chemotherapy and for the comparison of afatinib with cytotoxic chemotherapy.
AUTHORS' CONCLUSIONS
Erlotinib, gefitinib, afatinib and icotinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged PFS compared to cytotoxic chemotherapy. We found a beneficial effect of the TKI compared to cytotoxic chemotherapy in adverse effect and health-related quality of life. We found limited evidence for increased OS for the TKI when compared with standard chemotherapy, but the majority of the included trials allowed participants to switch treatments on disease progression, which will have a confounding effect on any OS analysis. Single agent-TKI remains the standard of care and the benefit of combining a TKI and chemotherapy remains uncertain as the evidence is based on small patient numbers. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, afatinib or icotinib and is associated with greater toxicity. There are no data supporting the use of monoclonal antibody therapy. Icotinib is not available outside China.
Topics: Afatinib; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bias; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cetuximab; Crown Ethers; ErbB Receptors; Erlotinib Hydrochloride; Female; Gefitinib; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Paclitaxel; Pemetrexed; Progression-Free Survival; Protein Kinase Inhibitors; Quality of Life; Quinazolines; Randomized Controlled Trials as Topic
PubMed: 33734432
DOI: 10.1002/14651858.CD010383.pub3 -
Journal of Comparative Effectiveness... Aug 2020To perform indirect treatment comparisons of entrectinib versus alternative fusion-positive non-small cell lung cancer treatments. Relevant studies with crizotinib... (Comparative Study)
Comparative Study
To perform indirect treatment comparisons of entrectinib versus alternative fusion-positive non-small cell lung cancer treatments. Relevant studies with crizotinib and chemotherapy as comparators of interest identified by systematic literature review were selected for matching-adjusted indirect comparison by feasibility assessment. Matching was based on known prognostic/predictive factors and scenario analyses were used for unreported confounders in comparator trials. Entrectinib yielded significantly better responses versus crizotinib in all scenarios (odds ratio [OR]: 2.43-2.74). Overall survival (hazard ratio: 0.47-0.61) and adverse event-related discontinuation (OR: 0.79-0.90) favored entrectinib. Progression-free survival was similar across treatments, except in one scenario. These results suggested improved outcomes with entrectinib versus crizotinib/chemotherapy and may help to make better informed treatment decisions.
Topics: Antineoplastic Agents; Benzamides; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Indazoles; Lung; Lung Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins
PubMed: 32648475
DOI: 10.2217/cer-2020-0063